Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system
Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while...
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| Veröffentlicht in: | Neuropsychopharmacology (New York, N.Y.) N.Y.), 2020-10, Vol.45 (11), p.1781-1792 |
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| creator | Lefevre, Emilia M Pisansky, Marc T Toddes, Carlee Baruffaldi, Federico Pravetoni, Marco Tian, Lin Kono, Thomas J Y Rothwell, Patrick E |
| description | Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits. |
| doi_str_mv | 10.1038/s41386-020-0643-x |
| format | Article |
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These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits.</description><identifier>ISSN: 0893-133X</identifier><identifier>EISSN: 1740-634X</identifier><identifier>DOI: 10.1038/s41386-020-0643-x</identifier><identifier>PMID: 32079024</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Abuse ; Adaptation ; Addictions ; Analgesics, Opioid ; Animal behavior ; Animals ; Brain ; Caudate-putamen ; Dopamine ; Drug tolerance ; Female ; Gene expression ; Genomes ; Male ; Mesolimbic system ; Mice ; Morphine ; Naloxone ; Narcotics ; Neostriatum ; Nucleus Accumbens ; Opioids ; Pharmaceutical Preparations ; Photometry ; Reinforcement ; Ribonucleic acid ; RNA ; Transcription ; Withdrawal</subject><ispartof>Neuropsychopharmacology (New York, N.Y.), 2020-10, Vol.45 (11), p.1781-1792</ispartof><rights>The Author(s), under exclusive licence to American College of Neuropsychopharmacology 2020.</rights><rights>The Author(s), under exclusive licence to American College of Neuropsychopharmacology 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-69b9ff0dac3e80e8e229e724fa97c9433e9529046dc63ceaf566a81679acda2a3</citedby><cites>FETCH-LOGICAL-c455t-69b9ff0dac3e80e8e229e724fa97c9433e9529046dc63ceaf566a81679acda2a3</cites><orcidid>0000-0003-0514-2510 ; 0000-0002-9462-7714 ; 0000-0002-6116-4549 ; 0000-0002-1388-3194</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608117/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608117/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,883,27907,27908,53774,53776</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32079024$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lefevre, Emilia M</creatorcontrib><creatorcontrib>Pisansky, Marc T</creatorcontrib><creatorcontrib>Toddes, Carlee</creatorcontrib><creatorcontrib>Baruffaldi, Federico</creatorcontrib><creatorcontrib>Pravetoni, Marco</creatorcontrib><creatorcontrib>Tian, Lin</creatorcontrib><creatorcontrib>Kono, Thomas J Y</creatorcontrib><creatorcontrib>Rothwell, Patrick E</creatorcontrib><title>Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system</title><title>Neuropsychopharmacology (New York, N.Y.)</title><addtitle>Neuropsychopharmacology</addtitle><description>Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits.</description><subject>Abuse</subject><subject>Adaptation</subject><subject>Addictions</subject><subject>Analgesics, Opioid</subject><subject>Animal behavior</subject><subject>Animals</subject><subject>Brain</subject><subject>Caudate-putamen</subject><subject>Dopamine</subject><subject>Drug tolerance</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Male</subject><subject>Mesolimbic system</subject><subject>Mice</subject><subject>Morphine</subject><subject>Naloxone</subject><subject>Narcotics</subject><subject>Neostriatum</subject><subject>Nucleus Accumbens</subject><subject>Opioids</subject><subject>Pharmaceutical Preparations</subject><subject>Photometry</subject><subject>Reinforcement</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Transcription</subject><subject>Withdrawal</subject><issn>0893-133X</issn><issn>1740-634X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kU1rFTEUhoMo9lr9AW4k4MZNNF-TTDaCFD8KhW5a6C7kZs60qTPJmGTK7b83l1uLuugqB_Kcl3POg9BbRj8yKvpPRTLRK0I5JVRJQXbP0IZpSYkS8uo52tDeCMKEuDpCr0q5pZR1WvUv0ZHgVBvK5QYtp7FCzutSQ4o4jdinWENc01pwWkIKA4bdksqaoRXOQ966CgUPeb0mcJd-woDd4Jbq9gEFh4jrDeAZSprCvA0eD2lxc4iAy32pML9GL0Y3FXjz8B6jy29fL05-kLPz76cnX86Il11XiTJbM450cF5AT6EHzg1oLkdntDdSCDAdN1SqwSvhwY2dUq5nShvnB8edOEafD7nLup1h8BBrdpNdcphdvrfJBfvvTww39jrdWa1oz5huAR8eAnL6tUKpdg7FwzS5CO06lgslqWBNQUPf_4fepjXHtp7lUistpO7k09TepGQdaxQ7UD6nUjKMjyMzavfW7cG6bdbt3rrdtZ53f-_62PFHs_gNl4-rpg</recordid><startdate>20201001</startdate><enddate>20201001</enddate><creator>Lefevre, Emilia M</creator><creator>Pisansky, Marc T</creator><creator>Toddes, Carlee</creator><creator>Baruffaldi, Federico</creator><creator>Pravetoni, Marco</creator><creator>Tian, Lin</creator><creator>Kono, Thomas J Y</creator><creator>Rothwell, Patrick E</creator><general>Nature Publishing Group</general><general>Springer International Publishing</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0514-2510</orcidid><orcidid>https://orcid.org/0000-0002-9462-7714</orcidid><orcidid>https://orcid.org/0000-0002-6116-4549</orcidid><orcidid>https://orcid.org/0000-0002-1388-3194</orcidid></search><sort><creationdate>20201001</creationdate><title>Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system</title><author>Lefevre, Emilia M ; 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These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>32079024</pmid><doi>10.1038/s41386-020-0643-x</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-0514-2510</orcidid><orcidid>https://orcid.org/0000-0002-9462-7714</orcidid><orcidid>https://orcid.org/0000-0002-6116-4549</orcidid><orcidid>https://orcid.org/0000-0002-1388-3194</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Abuse Adaptation Addictions Analgesics, Opioid Animal behavior Animals Brain Caudate-putamen Dopamine Drug tolerance Female Gene expression Genomes Male Mesolimbic system Mice Morphine Naloxone Narcotics Neostriatum Nucleus Accumbens Opioids Pharmaceutical Preparations Photometry Reinforcement Ribonucleic acid RNA Transcription Withdrawal |
| title | Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system |
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